In the senescent brain, microglial cells display a more activated phenotype and are hypersensitive to messages emerging from immune-to-brain signaling pathways. Thus, in old individuals with an infection, microglia over react to signals from the peripheral immune system and produce excessive levels of pro-inflammatory cytokines causing behavioral pathology including serious deficits in cognition. In several neurodegenerative diseases, microglial activation has been linked to intracellular reactive oxygen species that act as second messengers and stimulate redox-sensitive transcription factors (e.g., NFkB and AP-1) that control pro-inflammatory genes. Thus, regulating oxidative stress in microglia represents a potential therapeutic approach to not only reducing age-related oxidative damage but also the expression of pro-inflammatory genes, which has been shown to increase with age. To this end, the goal of the proposed research is to investigate if activation of the antioxidant response pathway in microglia reduces neuroinflammation in the senescent brain and prevents excessive production of pro-inflammatory cytokines during infection. The specific hypothesis is that dysfunctional Nuclear factor E2-related factor 2 (Nrf2) signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and that activation of Nrf2 with isothiocyanate sulforaphane (SFN)-a naturally occurring compound in cruciferous vegetables-will prevent the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. The research plan begins by assessing Nrf2 signaling, antioxidant response element (ARE) target genes, oxidative stress and inflammation in the brain of old mice and in microglia isolated from old mice. Subsequent studies will determine if activating Nrf2 with SFN reduces basal levels of oxidative stress and inflammation in brain as well as the reactivity of microglia to signals from the peripheral immune system during infection. Finally, we will determine if activating Nrf2 protects old mice against infection-related behavioral pathology and neuronal injury. This study will be the first to determine if dysfunctional Nrf2-ARE signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and if activation of the Nrf2-ARE pathway prevents the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine if oxidative stress caused by a dysfunctional antioxidant homeostatic response leads to microglial cell priming in the senescent brain. Our specific hypothesis is that dysfunctional Nuclear factor E2-related factor 2 (Nrf2) signaling is responsible for microglial cell priming and increased basal inflammation in the senescent brain and that activation of Nrf2 with sulforaphane, a naturally occurring compound in cruciferous vegetables, will prevent the harmful exaggerated neuroinflammatory response and resultant behavioral pathology during peripheral infection. The proposed research is important for developing new strategies for protecting cognitive health in older adults.